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Cardiovascular diseases and cancers are leading causes of morbidity and mortality. Reducing dietary saturated fat and replacing it with polyunsaturated fat is still the main dietary strategy to prevent cardiovascular diseases, although major flaws have been reported in the analyses supporting this approach. Recent studies introducing the concept of myocardial preconditioning have opened new avenues to understand the complex interplay between the various lipids and the risk of cardiovascular diseases. The optimal dietary fat profile includes a low intake of both saturated and omega-6 fatty acids and a moderate intake of omega-3 fatty acids. This profile is quite similar to the Mediterranean diet. On the other hand, recent studies have found a positive association between omega-6 and breast cancer risk. In contrast, omega-3 fatty acids do have anticancer properties. It has been shown that certain (Mediterranean) polyphenols significantly increase the endogenous synthesis of omega-3 whereas high intake of omega-6 decreases it. Finally, epidemiological studies suggest that a high omega-3 to omega-6 ratio may be the optimal strategy to decrease breast cancer risk. Thus, the present high intake of omega-6 in many countries is definitely not the optimal strategy to prevent cardiovascular disease and cancers. A moderate intake of plant and marine omega-3 in the context of the traditional Mediterranean diet (low in saturated and omega-6 fatty acids but high in plant monounsaturated fat) appears to be the best approach to reduce the risk of both cardiovascular diseases and cancers, in particular breast cancer.